Search Results (4)

Alzheimer’s disease (AD) has long proven to be a complex neurodegenerative disorder, with cholinergic dysfunction, oxidative stress, and neuroinflammation being just a few of its pathological features. The complexity of the disease requires a multitargeted treatment covering its many aspects. In the present investigation, an arylhydrazone derivative of 5-methoxyindole-2-carboxylic acid (5MeO), with in vitro strong antioxidant, neuroprotective and monoamine oxidase B-inhibiting effects, was studied in a scopolamine-induced Alzheimer-type dementia in rats. Using behavioral and biochemical methods, we evaluated the effects of 5MeO on learning and memory, and elucidated the mechanisms of these effects. Our experiments demonstrated that 5MeO had a beneficial effect on different types of memory as assessed by the step-through and the Barnes maze tasks. It efficiently restored the decreased by scopolamine brain-derived neurotrophic factor and acetylcholine levels and normalized the increased by scopolamine acetylcholine esterase activity in hippocampus. Most effective 5MeO was in counteracting the induced by scopolamine oxidative stress by decreasing the increased by scopolamine levels of lipid peroxidation and by increasing the reduced by scopolamine catalase activity. Blood biochemical analyses demonstrated a favorable safety profile of 5MeO, prompting further pharmacological studies suggesting 5MeO as a safe and efficient candidate in a multitargeted treatment of AD. Full article

This study presents a new 5-methoxy-1H-indole-2-carboxylic acid (MI2CA) polymorph investigated by single-crystal X-ray diffraction, infrared spectroscopy, and density functional theory (ωB97X-D) calculations employing two basis sets (6-31++G(d,p) and aug-cc-pVTZ). The compound crystallizes in the monoclinic system, space group P2₁/c (a = 4.0305(2) Å, b = 13.0346(6) Å, c = 17.2042(9) Å, β = 91.871(5)°, Z = 4). In the crystalline structure, the formation of cyclic dimers via double hydrogen bonds O−H⋯O between MI2CA molecules was observed. Interactions between the NH groups of the indole rings and the adjacent methoxy groups, as well as C–H⋯O contacts, significantly influence the spatial arrangement of molecules. The results from DFT calculations, including dimeric and trimeric structures, agree well with the experimental structural and spectroscopic data. Analysis of the infrared spectra confirms the conclusions drawn from X-ray diffraction studies and reveals differences between the IR spectra of the newly obtained polymorph and that reported earlier in the literature. This comprehensive study sheds some light on the MI2CA polymorphism and is important for a potential pharmacological applications of this compound. Full article

Given the importance of molecular structure in pharmacological activity and interaction with biological receptors, we conducted a study on the 3,4-dihydroxybenzaldehyde hydrazone derivative of 5-methoxy-indole carboxylic acid (5MICA) and a newly synthesised analogue bearing a 2-methoxy-4-hydroxyphenyl ring using single-crystal X-ray diffraction. We studied the ability of the two compounds to scavenge hypochlorite ions using luminol-enhanced chemiluminescence and their potential to modulate oxidative damage induced by iron on the biologically significant molecules lecithin and deoxyribose in order to evaluate possible antioxidant and prooxidant effects. The X-ray study revealed highly conserved geometry and limited rotation and deformation freedom of the respective indole and phenyl fragments. Interestingly, a conformational difference between the two independent molecules in the asymmetric unit of 3b was found. The X-ray study revealed a combination of hydrogen bonding interactions, short contacts, and π–π stacking stabilizing the specific three-dimensional packing of the molecules of 3a and 3b in the crystal structures. The three-dimensional packing of the molecules of 3b produced a zigzag layering projected along the c-axis. Both compounds effectively decreased luminol-dependent chemiluminescence in model systems with KO₂-produced superoxide. They displayed opposite effects when applied in a xanthine/xanthine oxidase system. The hydrazones of 5MICA do not trigger a prooxidant effect or subsequent toxicity under conditions of iron-induced oxidative stress. The 3,4-dihydroxy-substituted derivative demonstrated excellent radical scavenging properties in all model systems, making it the lead compound for the development of compounds with combined neuroprotective and antioxidant properties. Full article

In light of the known neuroprotective properties of indole compounds and the promising potential of hydrazone derivatives, two series of aldehyde-heterocyclic hybrids combining those pharmacophores were synthesized as new multifunctional neuroprotectors. The obtained derivatives of indole-3-propionic acid (IPA) and 5-methoxy-indole carboxylic acid (5MICA) had good safety profiles: Hemolytic effects < 5% (200 μM) and IC₅₀ > 150 µM were found in the majority of the SH-SY5Y and bEnd3 cell lines. The 2,3-dihydroxy, 2-hydroxy-4-methoxy, and syringaldehyde derivatives of 5MICA exhibited the strongest neuroprotection against H₂O₂-induced oxidative stress in SH-SY5Y cells and 6-OHDA-induced neurotoxicity in rat-brain synaptosomes. All the compounds suppressed the iron-induced lipid peroxidation. The hydroxyl derivatives were also the most active in terms of deoxyribose-degradation inhibition, whereas the 3,4-dihydroxy derivatives were able to decrease the superoxide-anion generation. Both series of compounds showed an increased inhibition of hMAO-B, with greater expression detected in the 5MICA hybrids. The in vitro BBB model with the bEnd3 cell line showed that some compounds increased the permeability of the endothelial monolayer while maintaining the tight junctions. The combined results demonstrated that the derivatives of IPA and 5MICA showed strong neuroprotective, antioxidant, MAO-B inhibitory activity and could be considered as prospective multifunctional compounds for the treatment of neurodegenerative disorders. Full article